Journal
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcimb.2022.932556
Keywords
antibiotic resistance; tuberculosis; bacterial genetics; chemical genetic profiling; CRISPRi; TnSeq; drug discovery
Categories
Funding
- NIH/NIAID [P01AI095208]
- Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program [W81XWH-17-1-0692]
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Despite significant advancements in the 20th century, tuberculosis (TB) remains a global health challenge, exacerbated by the COVID-19 pandemic. Improving TB chemotherapy through genetic and analytical tools can help identify and prioritize drug targets, leading to the rational design of treatment regimens that maximize bacterial killing and minimize treatment duration and relapse.
Therapeutic advances in the 20th century significantly reduced tuberculosis (TB) mortality. Nonetheless, TB still poses a massive global health challenge with significant annual morbidity and mortality that has been amplified during the COVID-19 pandemic. Unlike most common bacterial infectious diseases, successful TB treatment requires months-long regimens, which complicates the ability to treat all cases quickly and effectively. Improving TB chemotherapy by reducing treatment duration and optimizing combinations of drugs is an important step to reducing relapse. In this review, we outline the limitations of current multidrug regimens against TB and have reviewed the genetic tools available to improve the identification of drug targets. The rational design of regimens that sterilize diverse phenotypic subpopulations will maximize bacterial killing while minimizing both treatment duration and infection relapse. Importantly, the TB field currently has all the necessary genetic and analytical tools to screen for and prioritize drug targets in vitro based on the vulnerability of essential and non-essential genes in the Mtb genome and to translate these findings in in vivo models. Combining genetic methods with chemical screens offers a formidable strategy to redefine the preclinical design of TB therapy by identifying powerful new targets altogether, as well as targets that lend new efficacy to existing drugs.
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